↵⁎Reprint requests and correspondence: Dr. Gregg W. Stone, Department of Cardiology, Columbia University and Medical Center, New York-Presbyterian Hospital, The Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022

Abstract

Background Prior studies were not individually powered to generate reliable estimates of low-frequency safety endpoints or to characterize the long-term safety and efficacy profile of PES.

Methods The completed 5-year databases from the prospective, randomized, double-blind TAXUS I, II, IV, and V trials were pooled for a patient-level analysis.

Results The study population comprised 2,797 randomized patients (1,400 PES and 1,397 BMS). At the end of the 5-year study period, PES compared with BMS significantly reduced the rate of ischemia-driven target lesion revascularization (12.3% vs. 21.0%, p < 0.0001), with consistent reductions across high-risk subgroups and in patients with and without routine angiographic follow-up. There were no significant differences between the stent types in the 1-year or cumulative 5-year rates of death or myocardial infarction (MI). However, cardiac death or MI between 1 and 5 years was increased with PES (6.7% vs. 4.5%, p = 0.01), as was stent thrombosis (protocol definition: 0.9% vs. 0.2%, p = 0.007; ARC definition: 1.4% vs. 0.9%, p = 0.18).

Conclusions In this pooled patient-level analysis from the prospective, randomized, double-blind TAXUS trials, PES compared with BMS resulted in a durable 47% reduction in the 5-year rate of ischemia-driven target lesion revascularization in simple and complex lesions, with nonsignificant differences in the cumulative 5-year rates of death or MI. Between 1 and 5 years, however, the rates of cardiac death or MI and protocol-defined stent thrombosis were increased with PES.

Since its approval in the European Union in 2003 and the United States in 2004, the Taxus (Boston Scientific, Natick, Massachusetts) paclitaxel-eluting stent (PES) has been one of the most widely used drug-eluting stents (DES) in the world, with more than 6 million coronary implants to date (data on file, Boston Scientific). The PES was approved in most geographies based on the outcomes from 1 or more of 4 TAXUS trials (TAXUS I, II, IV, and V), in which PES was compared with an otherwise identical bare-metal stent (BMS) in increasingly complex lesions (1–8). Patients enrolled in each of these double-blind, prospective, randomized trials were followed for 5 years, with the blind maintained throughout the duration of the follow-up period. The primary powered endpoints of these trials varied from angiographic or intravascular ultrasound measures to clinical parameters depending on the purpose and size of each study. None of these trials, however, was individually powered to generate reliable estimates of low-frequency safety endpoints or to examine the long-term safety and efficacy profile of PES, especially as regards the rate and influence of late stent thrombosis and whether the early gains with PES compared with BMS are diminished over time (late catch-up).

Follow-up is now complete in all the TAXUS trials. Therefore, to comprehensively characterize the long-term safety and efficacy profile of PES, we performed a pooled, patient-level analysis from the TAXUS I, II, IV, and V trials. The following report represents the final principal analysis from the randomized TAXUS clinical trial development program.

Methods

Patients and study design

The TAXUS I, II, IV, and V trials enrolled patients between October 2000 and March 2004. The principal enrollment criteria, protocol procedures, and primary endpoints for these trials are shown in Table 1. The TAXUS II trial incorporated a dual randomization design in which both the commercialized slow-release and noncommercialized moderate-release formulations of the Taxus stent were evaluated; for the present analysis, only those patients enrolled in the TAXUS slow-release cohort were included. Similarly, the TAXUS VI trial, which evaluated the moderate-release formulation in complex lesions (9), is not included in the present analysis.

In each of these 4 trials, patients with native vessel coronary artery disease undergoing percutaneous coronary intervention (PCI) of a single lesion were prospectively randomized 1:1 in double-blind fashion to treatment with a slow-release PES versus an otherwise identical stainless steel BMS. The stent platform was the NIR stent (Boston Scientific) in TAXUS I and II, and the Express stent (Boston Scientific) in TAXUS IV and V. Whereas the TAXUS I, II, and IV studies were composed of patients with simple, de novo coronary artery lesions (reference vessel diameter [RVD]: 2.5 to 3.75 mm, and lesion length: 10 to 28 mm), the TAXUS V study population was enriched with patients with greater lesion complexity, including those with smaller diameter vessels (RVD: 2.25 to 2.5 mm) and longer lesions (≤46 mm). Patients with acute myocardial infarction (MI), left main disease, heavily calcified or tortuous lesions, thrombotic lesions, and lesions in bypass graft conduits were excluded from all 4 trials. PCI was performed per standard practice. Details regarding dual antiplatelet therapy prescription appear in Table 1. After discharge, all patients were followed at regular intervals through 5 years. Each study was approved by the institutional review board or ethics committee at each participating hospital, and all patients provided informed written consent.

In each trial, clinical events, including death, cardiac death, MI, TLR, TVR, and stent thrombosis were evaluated using an independent clinical events committee that was blinded to treatment allocations. In the pooled analysis, 79.2% (2,215 of 2,797) of patients were assigned to receive routine angiographic follow-up (at 6 months after procedure in TAXUS I and II and at 9 months in TAXUS IV and V). All angiographic and intravascular ultrasound data were evaluated by independent core laboratories blinded to stent assignment and clinical outcomes. The patients, investigators, research nurses, and all central committees and core laboratories remained blinded to randomized stent type for the entire 5-year follow-up duration.

Endpoints and definitions

Primary and secondary endpoints of the individual trials are summarized in Table 1. Clinical effectiveness endpoints measured in the trials included target lesion revascularization (TLR) and target vessel revascularization (TVR), and safety endpoints included death, cardiac death, MI (Q-wave, non–Q-wave), and stent thrombosis. The definitions of these endpoints have been previously described (5,10) and were consistent across all the trials to allow for pooling the data. Only ischemia-driven TLR and TVR events are reported. Stent thrombosis was prospectively defined by protocol as the clinical presentation of acute coronary syndrome with angiographic evidence of thrombosis, or acute MI in the distribution of the treated vessel, or death in the first 30 days post-procedure without other obvious cause and in the absence of available angiography. Stent thrombosis was also retrospectively adjudicated by the clinical events committee according to the definite or probable criteria of the Academic Research Consortium (ARC). By ARC definition, an acute coronary syndrome with angiographic or autopsy evidence of thrombus or occlusion within or adjacent to a stent is considered “definite” stent thrombosis, whereas an unexplained death within 30 days after stent implantation or acute MI involving the target vessel territory without angiographic confirmation is considered “probable” stent thrombosis (8).

Statistical analysis

Poolability of the TAXUS I, II, IV, and V databases was confirmed using the Breslow-Day test, which assessed the homogeneity of the odds ratios of safety and efficacy endpoints across the different studies. Binary or categorical variables are expressed as percentages and were compared by chi-square or Fisher exact test, whereas continuous variables are expressed as mean ± SD and were compared by Student t tests. Time-to-event data are presented as Kaplan-Meier estimates for clinical outcomes and were compared by the log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were derived from univariate Cox models for the comparisons between groups. Landmark time-to-event analyses were also performed in which all patients alive at 1-year follow-up were considered event-free, regardless of whether an earlier event had occurred. All analyses were evaluated in the intent-to-treat population, consisting of all patients enrolled in each of the respective trials, regardless of treatment received. For the time-to-event analyses, patients were censored at the time of death, withdrawal from the study, or at last follow-up.

The independent effects of baseline risk factors on the endpoints of TLR and cardiac death or MI were assessed using Cox proportional hazards regression. The baseline variables considered for entry into the model were age, sex, current smoking, medically treated diabetes, hypertension, hyperlipidemia, congestive heart failure, RVD, diameter stenosis, lesion length, lesion location in the left anterior descending artery, and randomization to PES versus BMS. All variables with a univariate p < 0.1 value were entered into the multivariable model, with the exception of stent randomization, which was forced into the model. All analyses were performed using SAS (version 9.0, Cary, North Carolina). Statistical significance was defined as p < 0.05, and all p values were 2-sided.

Results

Patients and procedures

The pooled study population comprised 2,797 randomized patients, of which 1,400 were assigned to PES and 1,397 were assigned to BMS. The baseline clinical characteristics were well matched between the groups (Table 2). Mean age was 62.5 years, 28.4% of patients were female, 25.5% had diabetes mellitus, and 32.7% presented with unstable angina. Core angiographic laboratory measures of the lesions randomized to PES and BMS were also comparable (Table 2). The mean RVD and lesion length were 2.73 mm and 14.7 mm, respectively. Procedural characteristics and long-term dual antiplatelet therapy use were well balanced between the groups (Table 3). Although aspirin usage was high throughout the 5-year follow-up duration, thienopyridine usage was <50% at 1 year and beyond.

Angiographic outcomes

Among patients assigned to routine angiographic follow-up, follow-up angiography was completed at 6 to 9 months in 1,113 of 1,400 PES patients (79.5%) and in 1,102 of 1,397 BMS patients (78.9%). Compared with BMS, PES resulted in significantly less late loss and a larger follow-up minimal luminal diameter in-stent, at both the proximal and distal stent margins, and over the entire analysis segment (Table 4) (11). Binary angiographic restenosis was reduced from 26.9% with BMS to 9.0% with PES in-stent (relative risk: 0.33, 95% CI: 0.27 to 0.42; p < 0.0001), and from 29.0% with BMS to 12.9% with PES over the entire analysis segment (relative risk: 0.45, 95% CI: 0.37 to 0.54; p < 0.0001). When restenosis did occur, its length was significantly shorter and its morphology less complex with PES than with BMS.

Clinical outcomes: efficacy

Treatment with PES versus with BMS significantly reduced the 5-year rates of TLR and TVR, including reductions in the need for both repeat PCI and coronary artery bypass graft (CABG) procedures during follow-up (Fig. 1A, Table 5). The peak reduction in TLR with PES was achieved within the first year after randomization, after which subsequent revascularization events accrued equally with both stents (Fig. 2A). The absolute and relative reductions in TLR with PES versus BMS were comparable in patients in whom routine protocol angiographic follow-up was and was not intended (Fig. 3). By multivariable analysis, treatment with PES rather than BMS was an independent predictor of a 47% reduction in TLR at 5 years (Table 6). Among patients treated with PES, smaller RVD, greater lesion length, and younger age were independent correlates of 5-year TLR. Finally, the relative reduction in the 5-year rate of TLR with PES versus with BMS was consistent across 7 high-risk patient and lesion subgroups examined, including patients with diabetes mellitus (Fig. 4A).

Kaplan-Meier estimates (with SE bars) and hazard ratios (HR) are displayed for target lesion revascularization (A); cardiac death or myocardial infarction (B); definite or probable stent thrombosis as defined by the Academic Research Consortium criteria (C); and stent thrombosis according to the protocol definition (D). There were no significant interactions between stent types with time to follow-up for any of the results reported except for target lesion revascularization, for which a marginal p value of 0.049 was present. BMS = bare-metal stent(s); CI = confidence interval; PES = paclitaxel-eluting stent(s).

Kaplan-Meier estimates (with SE bars) and hazard ratios are displayed in the intervals from 0 to 1 year post-procedure and from 1 to 5 years post-procedure for target lesion revascularization (A); cardiac death or myocardial infarction (B); definite or probable stent thrombosis defined by the Academic Research Consortium criteria (C); and stent thrombosis according to the protocol definition (D). Abbreviations as in Figure 1.

Multivariable Predictors of Adverse Events Through 5 Years in the Pooled TAXUS Trials

Clinical outcomes: safety

There were no statistically significant differences in the cumulative rates of death (all-cause or cardiac), MI, or cardiac death or MI between the 2 stent types at either 1 year or at the end of the 5-year follow-up period (Fig. 1B, Tables 5 and 6). However, whereas the hazard curves for the composite rate of cardiac death or MI were superimposable within the first year, after year 1, the curves diverged (Fig. 2B) due to a significant increase in MI (3.8% vs. 2.3%, p = 0.03) and a nonsignificant increase in cardiac death (3.5% vs. 2.5%, p = 0.15) with PES between years 1 and 5 of follow-up. As a result, a significant increase in the composite rate of cardiac death or MI with PES compared with BMS emerged after the first year in this landmark analysis (Fig. 2B), driven by an increase in target vessel MI (2.1% vs. 1.2%, p = 0.01), with trends present for greater Q-wave MI (1.0% vs. 0.7%, p = 0.38) and non–Q-wave MI (2.9% vs. 1.8%, p = 0.08).

The relative difference in the 5-year rate of cardiac death or MI between PES and BMS was consistent among most subgroups examined (Fig. 4B). However, a significant interaction was present between lesion length and stent type such that the 5-year rate of cardiac death or MI was significantly increased with PES in lesions ≥18 mm in length (by core laboratory analysis), whereas cardiac death or MI occurred at nearly identical rates with PES and BMS in shorter lesions. Similarly, the 5-year rates of death or MI were comparable between PES and BMS when 1 stent was used, but increased with implantation of multiple stents.

At the completion of the 5-year follow-up period, there was a statistically significant increase in stent thrombosis with PES versus with BMS according to the pre-specified protocol definition of stent thrombosis. A similar trend was apparent when stent thrombosis was defined according to the ARC definite or probable criteria, although the difference did not reach statistical significance (Figs. 1C and 1D, Table 7). No significant difference in stent thrombosis between the 2 stents was evident within the first year; the increase in protocol-defined stent thrombosis with PES occurred between years 1 and 5 of follow-up (Fig. 2D). In patients treated with PES versus BMS, the 5-year rates of protocol-defined stent thrombosis in lesions ≥18 mm were 1.8% versus 0.6%, respectively (HR: 2.97, 95% CI: 0.6 to 14.72), and in lesions <18 mm were 1.6% versus 0.9%, respectively (HR: 1.81, 95% CI: 0.8 to 4.09; p value for interaction = 0.59).

Discussion

The principal findings from the present report, representing the final 5-year analysis from the TAXUS clinical trial development program, are that in patients undergoing PCI of a single de novo lesion of varying complexity, treatment with the slow-release PES versus an otherwise identical BMS resulted in: 1) significant 1-year reductions in ischemia-driven TLR and TVR in simple and complex patients and lesions, differences that were maintained throughout 5 years of follow-up, with no evidence of late catch-up apparent; 2) nonsignificant differences in the cumulative rates of all-cause mortality, cardiac mortality, MI, and cardiac death or MI at the end of the 5-year follow-up period; 3) an increase in the 5-year cumulative rate of stent thrombosis, which reached statistical significance when defined by the pre-specified protocol definition of stent thrombosis, but not by the ARC definite or probable definition; and 4) similar rates of cardiac death or MI and protocol-defined stent thrombosis within the first year after stent implantation, but a significant increase in these endpoints between 1 and 5 years of follow-up.

Among 2,215 randomized patients in whom routine angiographic follow-up between 6 and 9 months was performed, treatment with PES rather than with BMS markedly reduced the rates of both in-stent and in-segment binary restenosis, as well as the length and complexity of the restenotic segment, resulting in significant reductions in the need for ischemia-driven TLR procedures (both repeat PCI and CABG) over the 5-year follow-up period. The absolute 3.2% reduction in the requirement for CABG in patients treated with PES rather than BMS (number needed to treat = 31 to prevent 1 CABG) is of particular note. Furthermore, a major goal of the current study was to examine the clinical durability of the antirestenotic effect of PES, as incremental angiographic late loss in DES beyond 1 year has been described (although to a lesser extent with PES than rapamycin-analogue-eluting stents) (12–16). In the present analysis, the maximal reduction in TLR with PES versus with BMS was achieved within the first year after PCI and remained stable thereafter, with no clinical evidence of late catch-up. Also of note, the relative reduction in TLR with PES versus with BMS was consistent across numerous high-risk subgroups, including patients with diabetes, which in this regard may differentiate PES from rapamycin-analogue-eluting stents (17,18). Among patients receiving PES, there was a relative increase in TLR in small vessels, long lesions, and younger patients (the latter likely due to a higher threshold for repeat invasive procedures in elderly patients), which are subgroups that may benefit from a more potent DES (19–21).

Routine angiographic follow-up was performed in a substantial proportion of patients in the TAXUS trials and is a protocol-specific event that may distort the magnitude of differences in the perceived effectiveness between stents by differentially invoking repeat revascularization procedures that might otherwise not have occurred (the “oculostenotic reflex”) (22,23). Specifically, we have previously reported that routine angiographic follow-up in studies of PES versus BMS may increase the absolute, but not the relative, differences in TLR at 1 to 2 years between the devices (24,25). However, in the present analysis, both the relative and absolute reductions in TLR with PES versus with BMS at 5 years were comparable in both patients with and without intended angiographic follow-up, suggesting that longer-term follow-up may ameliorate the confounding effects of the oculostenotic reflex.

The present pooled analysis was undertaken, in part, to enlarge the sample size beyond any individual trial to afford increased power to examine whether differences in the rates of low-frequency safety events exist between PES and BMS. In this regard, among 2,797 randomized patients, there were no statistically significant differences between the stent types in the cumulative rates of all-cause mortality, cardiac mortality, MI, or the composite of cardiac death or MI over the 5-year follow-up period, despite decreasing dual antiplatelet therapy use over time. However, whereas the rates of stent thrombosis were similar with both stents within the first year, extended follow-up revealed an increased frequency of very late stent thrombosis with PES. This difference became statistically significant at the end of the 5-year follow-up period according to the pre-specified study protocol definition, but not by the more commonly used ARC definite or probable definition. The discordance may be explained by the fact that the ARC criteria for stent thrombosis are more sensitive than the protocol definition is. There were 33 stent thrombosis episodes according to the protocol definition, as opposed to 52 according to ARC (38 of which were “definite”). Which of these definitions is closer to the “truth” is uncertain. Regardless, the observation of an increased rate of very late stent thrombosis with PES versus BMS suggests a difference in chronic vascular responses between the 2 stent types, with a more quiescent late profile for BMS compared with PES, in which incomplete healing and detrimental polymer reactions have been observed (26). Finally, the hazard curves for stent thrombosis between the stent types (by both definitions) ceased to diverge after 4 years of follow-up; longer-term surveillance in even greater numbers of patients than in the present study is required to confirm this observation.

Although there were no statistically significant increases in the overall 5-year rates of cardiac death or MI between the devices, a significant increase in the composite rate of cardiac death or MI with PES versus with BMS emerged between years 1 and 5 of follow-up in the landmark analysis. In part, this finding may be explained by the increased rate of very late stent thrombosis that occurred with PES versus with BMS in this period. By interaction testing, the increase in cardiac death or MI with PES versus with BMS between 1 and 5 years was confined to patients in whom longer lesions (≥18 mm by quantitative coronary angiography) were treated with PES. We have previously reported a higher rate of periprocedural MI due to side branch compromise when multiple PES are implanted in long lesions or for bailout indications (8). In the present study, the absolute difference in the rate of protocol-defined stent thrombosis was also greater with PES than with BMS treatment of longer compared with shorter lesions. As findings from subgroup analyses, these observations should be considered hypothesis-generating, requiring validation in other large-scale studies. Moreover, even with 2,797 randomized patients, the role of chance cannot be excluded. In this regard, among 3,006 patients with ST-segment elevation MI randomized to PES versus BMS in the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial (representing an even higher-risk cohort than in the present study), there were no significant differences between stent types in the 3-year rates of death or MI (11.8% vs. 11.5%, respectively; p = 0.88) or ARC definite or probable stent thrombosis (4.8% vs. 4.3%, respectively; p = 0.63) (27).

Study limitations

Relative limitations and strengths of the present analysis should be placed in perspective. Although the 4 TAXUS trials were poolable according to commonly accepted criteria, the patient and lesion characteristics of the individual studies varied; it is always preferable to achieve adequate power through 1 large trial rather than by combining studies. Nonetheless, the present analysis is the largest systematic dataset to date examining coronary DES outcomes with uniform study monitoring and data management processes, common definitions, and use of matched active controls. Additional strengths include the fact that randomization in each of the component trials was double-blind, and all patients were followed for 5 years (with the blind maintained throughout the follow-up period). Pooling across a range of lesion complexity may result in treatment effects in high-risk lesions (whether positive or negative) being masked by the larger body of lower-risk lesions. The results of the present analysis also apply only to those patient and lesion types enrolled, as well as to the specific stents studied. In this regard, although the relative safety and efficacy results with the PES NIR and Express platforms were found to be comparable in heterogeneity testing, vascular responses and clinical outcomes with the Taxus Liberté stent (not evaluated in the present randomized trials) may be improved in complex lesions compared with responses and outcomes for the Taxus Express platform (28,29). Finally, whether the long-term safety and efficacy of PES have been improved by the second-generation everolimus-eluting stent will be determined by the 5-year follow-up results from the randomized, large-scale SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions) and COMPARE (Second-Generation Everolimus-Eluting and Paclitaxel-Eluting Stents in Real-Life Practice) trials (19–21).

Conclusions

The present patient-level pooled analysis from the TAXUS I, II, IV, and V trials has demonstrated that in patients without ST-segment elevation MI, the slow-release PES compared with an otherwise identical BMS resulted in a significant reduction in ischemia-driven TLR that was sustained over 5 years, with nonsignificant differences in the cumulative 5-year rates of all-cause mortality, cardiac mortality, and MI. Between 1 and 5 years of follow-up, the composite rate of cardiac death or MI was significantly increased with PES versus with BMS, as was the occurrence of stent thrombosis. Ongoing studies are being performed to determine whether the late safety profile of PES (and other DES) might be further improved with long-term administration of dual antiplatelet therapy (30).

Footnotes

The TAXUS trials and the present analysis were funded by Boston Scientific, Natick, Massachusetts. Dr. Stone has served on the scientific advisory boards for and has received honoraria from Boston Scientific and Abbott Vascular, and is a consultant to Medtronic. Dr. Ellis has served as a consultant for Boston Scientific and Abbott Vascular. Dr. Colombo has served on the scientific advisory board for Boston Scientific. Dr. Grube has served on the scientific advisory board and been a member of the Speakers' Bureau for Boston Scientific. Dr. Popma has served on the scientific advisory board for and has received research grants from Boston Scientific. Drs. Uchida, Bleuit, and Dawkins are full-time employees of Boston Scientific. Dr. Russell was previously a full-time employee at Boston Scientific.

(2009) Final 5-year results of the TAXUS II trial: a randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for de novo coronary artery lesions. Circulation120:1498–1504.

(2008) Reduced risk of restenosis in small vessels and reduced risk of myocardial infarction in long lesions with the new thin-strut TAXUS Liberté stent: 1-year results from the TAXUS ATLAS program. J Am Coll Cardiol Intv1:699–709.